Moreover, we showed that specific IFN-α expression in the β cells of IFNα-INS1CreERT2 transgenic mice led to development of T1D that was preceded by increased islet DNA hydroxymethylation through a PNPT1/TET2-dependent mechanism.
Treating pre-diabetic NOD mice with cyclic guanyl-adenyl dinucleotide (cGAMP) to activate STING directly delayed T1D onset and stimulated interferon-αβ (IFN-αβ), while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN-αβ in NOD mice.
Second, a significant correlation of antibody-mediated IFNα neutralization with an absence of disease in patients highly disposed to Type I diabetes has been challenged because of a claimed failure to replicate our findings (Landegren, 2019).
Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes.
These observations suggest that IFN-α-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-α inhibitors might need to be used at very early stages of the disease to be effective.
In the libraries, the frequency of islet Ag-specific CD45RO<sup>+</sup>IFN-γ<sup>+</sup>CD8<sup>+</sup> T cells was higher in patients with T1D compared with healthy control subjects.
The profound elevation in IFN-I and the IFN gene signature observed in some forms of T1D are also seen in a novel group of human autoimmune and autoinflammatory diseases called interferonopathies.
An additional clue that links T1-IFN to T1D is that these cytokines are a known constituent of the autoinflammatory milieu within the pancreas of patients with T1D.
Essential components of the innate immune antiviral response, including type I interferon (IFN) and IFN receptor-mediated signaling pathways, are candidates for determining susceptibility to human type 1 diabetes.
These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
The identified dysregulation in the IFN-α-induced antiviral response in T1D patients, especially in early childhood, could be one of the factors affecting T1D development.
In the present report, we have adopted a linkage disequilibrium (LD) mapping approach to test for an association between T1D and three regions encompassing 13 interferon alpha (IFNA) genes, interferon omega-1 (IFNW1), interferon beta-1 (IFNB1), interferon gamma (IFNG) and the interferon consensus-sequence binding protein 1 (ICSBP1).